Normal outcome of pregnancy with ongoing treatment with natalizumab.

BACKGROUND: Treatment of multiple sclerosis (MS) with natalizumab during pregnancy is not recommended due to potential risks for the foetus. Despite strong advice accidental pregnancies occur. CASE: A 32-year old woman with MS since the age of 26 was treated with natalizumab since January 2008. Treatment was stopped April 2011 due to pregnancy plans, but was restarted following an MS relapse. The patient was thoroughly informed about potential foetal risks, but nevertheless she one year later disclosed that she was pregnant in gestational week 15. Treatment was continued, since the first trimester had passed. The pregnancy course was normal and a healthy daughter was born at full gestational term. CONCLUSIONS: This is the second known case where natalizumab treatment continued throughout the whole gestational period.

Assessing tissue damage in multiple sclerosis: a biomarker approach.

OBJECTIVES: Magnetic resonance imaging (MRI) of the brain and spinal cord is the gold standard for assessing disease activity in multiple sclerosis (MS). MRI is an excellent instrument for determination of accumulated damage to the brain and spinal cord, but tells us little about ongoing tissue damage. In this study, biomarkers of oligodendrocyte, axonal and astrocyte injury were related to MRI and clinical findings and used to assess tissue damage in MS. MATERIALS AND METHODS: Cerebrospinal fluid from 44 patients with relapsing-remitting MS, 20 with secondary progressive MS and 15 controls were investigated with ELISA to determine levels of myelin basic protein (MBP), neurofilament light (NFL) and glial fibrillary acidic protein (GFAp). Patients underwent MRI of the brain and spinal cord, and gadolinium enhancing lesions, T1 lesions and T2 lesions were counted. RESULTS: Patients in clinical relapse and patients with nonsymptomatic gadolinium enhancing lesions had high levels of MBP and NFL, indicating ongoing damage to oligodendrocytes and axons. The level of MBP dropped quickly within a week from the onset of a relapse, whereas NFL remained elevated for several weeks and GFAp slowly rose during the course of a relapse. Relapsing-remitting MS patients without gadolinium enhancing lesions had values of MBP, NFL and GFAp similar to controls, while patients with secondary progressive disease had moderately increased values of all biomarkers. CONCLUSIONS: Analysis of MBP, NFL and GFAp provides direct means to measure tissue damage and is a useful addition to our methods for evaluation of MS.

Time to secondary progression in patients with multiple sclerosis who were treated with first generation immunomodulating drugs.

BACKGROUND: It is currently unknown whether early immunomodulatory treatment in relapsing-remitting MS (RRMS) can delay the transition to secondary progression (SP). OBJECTIVE: To compare the time interval from onset to SP in patients with RRMS between a contemporary cohort, treated with first generation disease modifying drugs (DMDs), and a historical control cohort. METHODS: We included a cohort of contemporary RRMS patients treated with DMDs, obtained from the Swedish National MS Registry (disease onset between 1995-2004, n = 730) and a historical population-based incidence cohort (onset 1950-64, n = 186). We retrospectively analyzed the difference in time to SP, termed the "period effect" within a 12-year survival analysis, using Kaplan-Meier and Cox regression analysis. RESULTS: We found that the "period" affected the entire severity spectrum. After adjusting for onset features, which were weaker in the contemporary material, as well as the therapy initiation time, the DMD-treated patients still exhibited a longer time to SP than the controls (hazard ratios: men, 0.32; women, 0.53). CONCLUSION: Our results showed there was a longer time to SP in the contemporary subjects given DMD. Our analyses suggested that this effect was not solely driven by the inclusion of benign cases, and it was at least partly due to the long-term immunomodulating therapy given.

Bilateral and recurrent optic neuritis in multiple sclerosis.

OBJECTIVE: To assess the frequency of bilateral and recurrent optic neuritis (ON) in multiple sclerosis (MS) and to compare these results with epidemiological data of ON in neuromyelitis optica (NMO) and recurrent ON without other signs of disease. METHODS: We identified 472 patients with diagnosis of MS from the Swedish Multiple Sclerosis Register. These patients were evaluated for the presence of ON and whether the ON was the presenting symptom of MS; unilateral or bilateral; monophasic or recurrent. RESULTS: Twenty-one percent presented with ON as their first manifestation of MS. The proportion of patients developing a second attack of ON before demonstration of other manifestations of MS was 5.5% and the frequency of recurrent bilateral ON as the presenting symptom was 3.8%. Only two patients presented with simultaneously appearing bilateral ON corresponding to 0.42%. CONCLUSION: Recurrent ON, whether unilateral or bilateral, is a common presentation of MS. As MS is a much more common disease than NMO, care must be taken when evaluating the work-up of patients with recurrent ON. In some cases repeated MRI and lumbar punctures are warranted to improve diagnostic accuracy, even in the presence of the serological marker NMO-IgG.

Short-term prediction of secondary progression in a sliding window: A test of a predicting algorithm in a validation cohort.

INTRODUCTION: The Multiple Sclerosis Prediction Score (MSPS, www.msprediction.com) estimates, for any month during the course of relapsing-remitting multiple sclerosis (MS), the individual risk of transition to secondary progression (SP) during the following year. OBJECTIVE: Internal verification of the MSPS algorithm in a derivation cohort, the Gothenburg Incidence Cohort (GIC, n = 144) and external verification in the Uppsala MS cohort (UMS, n = 145). METHODS: Starting from their second relapse, patients were included and followed for 25 years. A matrix of MSPS values was created. From this matrix, a goodness-of-fit test and suitable diagnostic plots were derived to compare MSPS-calculated and observed outcomes (i.e. transition to SP). RESULTS: The median time to SP was slightly longer in the UMS than in the GIC, 15 vs. 11.5 years (p = 0.19). The MSPS was calibrated with multiplicative factors: 0.599 for the UMS and 0.829 for the GIC; the calibrated MSPS provided a good fit between expected and observed outcomes (chi-square p = 0.61 for the UMS), which indicated the model was not rejected. CONCLUSION: The results suggest that the MSPS has clinically relevant generalizability in new cohorts, provided that the MSPS was calibrated to the actual overall SP incidence in the cohort.

Sympathetic response to oral carbohydrate administration. Evidence from microelectrode nerve recordings.

Microneurography was used to measure sympathetic outflow in human muscle nerves (MSA) for up to 90 min after the ingestion of 100 g D-glucose, 75.8 g D-xylose, intravenous D-glucose (0.35 g/kg), and 300 ml water. 19 healthy subjects were examined using a microelectrode positioned in the right peroneal nerve. MSA increased from 21 +/- 0.9 bursts/min at rest to 36.9 +/- 4.3 bursts/min 30 min after ingestion of D-glucose and from 18.9 +/- 2.9 to 26.3 +/- 3.4 bursts/min 30 min after D-xylose. The increase in MSA was already significant by 15 min. MSA had not returned to the basal level after 90 min. Neither intravenous D-glucose nor water intake enhanced MSA. MSA increased in parallel with plasma norepinephrine, and a significant correlation (r = 0.55; P less than 0.001) was observed between the plasma insulin concentration and MSA after D-glucose ingestion. In three subjects the outflow of sympathetic nerve activity to the skin was examined after oral D-glucose and no change was observed, emphasizing the differentiated nature of the sympathetic nerve response to carbohydrate. Multiple factors such as insulin alone, hemodynamic adjustment to splanchnic vasodilation, and gastrointestinal distension are probably involved in the increased muscle nerve sympathetic outflow after carbohydrate ingestion.

Sympathetic outflow in human muscle nerves increases during hypoglycemia.

The normal response to insulin-induced hypoglycemia bears many characteristics of activation of the sympathetic nervous system. In this study, the impulse pattern of muscle nerve sympathetic activity (MSA) involved in cardiovascular homeostasis was identified by microneurography in the peroneal nerve of seven healthy and two adrenalectomized subjects. After recordings at rest and an intravenous injection of 0.15 IU insulin/kg body wt (0.10 IU insulin/kg body wt in adrenalectomized subjects), MSA was followed for 90 min. Nadir of hypoglycemia (2.0 +/- 0.1 mM) was reached at 30 min. All subjects, including the two adrenalectomized subjects, exhibited an increase of MSA, which peaked at the glucose nadir. The time course of MSA increase was a mirror image of the blood glucose curve. This directly measured increase of MSA may be part of the hemodynamic adjustment to the fall in plasma volume known to occur in hypoglycemia. Another possible cause is direct stimulation of central sympathetic motoneurons.

Sympathetic outflow to the hand in patients with Raynaud's phenomenon.

Microelectrode recordings of skin nerve sympathetic activity were made in the median nerve supplying the right hand of nine patients with Raynaud's phenomenon and 10 control subjects. With subjects warmed up (finger temperature 33 to 34 degrees C) different manoeuvres were used to evoke strong, single sympathetic bursts, giving rise to vasoconstriction of the same magnitude in patients and control subjects. Immersion of the contralateral hand in ice water for 1 min elicited an increase in sympathetic outflow without any difference between patients and control subjects. It is concluded that neither hypersensitivity of the vessels to strong sympathetic bursts, nor abnormal increase of sympathetic outflow following shortlasting, local cold exposure, was present in the patients. A possible change of the functional relationship between nerve and vessel, the importance of which is uncertain, was observed in the patient group. The study provides direct evidence against a primary sympathetic hyperfunction and indirect support for a local fault mechanism in Raynaud's phenomenon.

Sympathetic activity and blood pressure increases with bladder distension in humans.

Microneurographic recordings of muscle nerve sympathetic activity, which is governed by baroreceptors and involved in blood pressure regulation, were made in the peroneal nerve in 16 healthy volunteers during physiological bladder distension. When the urge to urinate was pronounced, sympathetic outflow increased from a baseline level of 16.3 +/- 1.7 to 23.2 +/- 1.9 bursts/min (mean +/- SEM, p less than 0.01). There was a concomitant significant rise in both systolic and diastolic blood pressure, from 125 +/- 2/74 +/- 2 to 140 +/- 4/84 +/- 3 mm Hg. After micturition, sympathetic activity and blood pressure returned toward initial values. It is concluded that 1) increased sympathetic outflow contributed to the rise in blood pressure, 2) there is a vesicovascular response mediated by sympathetic vasoconstrictor neurons in humans corresponding to mechanisms observed in animals, and 3) the described functional relation between bladder distension and sympathetic vasoconstrictor activity probably plays a role in clinical conditions such as autonomic dysreflexia in humans with cervical spinal cord lesions and nocturnal micturition syncope.

Treatment of the Guillain-Barré syndrome by plasmapheresis.

Treatment by plasmapheresis was performed in eight adult patients with the Guillain-Barré syndrome. One patient with a chronic relapsing form underwent four separate courses of plasmapheresis and her condition improved rapidly each time. Of seven patients with acute Guillain-Barré syndrome, the condition of three improved markedly, in one partially, and in three it did not improve in association with treatment. There were no apparent differences concerning clinical and neurophysiologic parameters between those whose conditions improved and those whose conditions did not.

Continuous recording of muscle nerve sympathetic activity during percutaneous transluminal angioplasty in renovascular hypertension in man.

We have previously shown that during percutaneous transluminal renal angioplasty (PTRA) there is a transient increase in plasma renin activity (PRA) that is partly mediated by adrenergic beta-receptors. Despite a concomitant increase in plasma aldosterone, no increase in blood pressure occurred. The aim of this study was to record sympathetic outflow in man during PTRA as reflected by muscle nerve sympathetic activity and arterial plasma noradrenaline. Nine patients with hypertension and unilateral renal artery stenosis underwent PTRA by the Grüntzig technique and simultaneous microelectrode recording of muscle nerve sympathetic activity in the peroneal nerve. Blood pressure and heart rate were recorded and blood specimens were drawn for determination of noradrenaline and PRA. During total occlusion of the renal artery, muscle nerve sympathetic activity and the heart rate were unchanged. In the first 6 min after occlusion PRA increased transiently, but there was no significant change in muscle nerve sympathetic activity, arterial noradrenaline, heart rate or blood pressure. From 10 min after PTRA, muscle nerve sympathetic activity was significantly increased and after 40 min there was a significant increase in noradrenaline. The heart rate remained unchanged throughout the procedure, but the blood pressure decreased progressively and the diastolic blood pressure was significantly reduced at 40 min, indicating successful dilation. Despite activation of the renin-angiotensin-aldosterone system and the sympathetic nervous system, two strong pressor systems, the only circulatory reaction was a decrease in diastolic blood pressure. These findings indicate simultaneous activation of a potent depressor mechanism during PTRA.

Serum antibodies to peripheral nerve tissue in acute Guillain-Barré syndrome in relation to outcome of plasma exchange.

Mixed haemagglutination and complement fixation tests were used to detect serum antibodies to peripheral nerve in 36 patients with acute Guillain-Barré syndrome. Twenty patients were treated with plasma exchange, 16 served as controls. A significant antibody titre was found in 19 patients with the haemagglutination test; 30 had complement-fixing antibodies. Patients lacking complement-fixing antibodies were less disabled at entry (P less than 0.01). However, there was no correlation between the course of the disease and any of the antibodies in the two patient groups. The two tests were therefore not able to select patients for treatment by plasma exchange.

The clinical effect and the effect on serum IgG antibodies to peripheral nerve tissue of plasma exchange in patients wit Guillain-Barré syndrome.

The mixed haemagglutination technique was used to demonstrate IgG antibodies to peripheral nerve tissue in sera from patients with the Guillain-Barré syndrome. The clinical effect and the effect on the antibodies of plasma exchange were examined in 18 patients. Neurological examination with muscle testing and neurophysiological examination of the patients were performed before and immediately after plasma exchange. Before the exchange antibodies were detected in sera from 11 of the patients. These patients showed clinical improvement during the treatment. After plasma exchange, antibodies were detected in sera from only two of the patients. The seven patients without detectable antibodies showed no clinical improvement.

Variability of sensory threshold determination in clinical use.

The variability of perception threshold determination for vibration, tactile stimuli and thermal stimuli, with instruments intended for clinical use, was studied in 13 healthy subjects and 27 patients with chronic polyneuropathy. Normal thresholds for tactile and thermal stimuli were determined in 51 healthy subjects. Determinations were made for vibration on hand, lower leg and foot, for touch on pulp of forefinger and great toe and for temperature on hand and foot. Normal thresholds for both tactile and thermal stimuli were age-dependent. Short-term variation, with intervals of some minutes between determinations, remained within 8-18% change from first value. Long-term variation, with intervals of days to some weeks, was pronounced for all types of threshold, with extremes of -90% and +256% change from first determination in 3 or 4 subsequent determinations. Variation was most marked for tactile stimuli and smallest for vibration, but magnitude and pattern of variation was similar for all sensory modalities and for both patients and healthy subjects. Confidence intervals, derived from analysis of variance, showed than as an average a change of less than -60% or greater than +150% from the initial value was needed to ascertain with 95% probability that a subsequent value will reflect a true change of sensory threshold. Basing every threshold value on 2 or more measurements per occasion will reduce the confidence interval. The main cause of variability seems to be central processing mechanisms, i.e. the psychological variability. With proper attention to the variability, sensory threshold determinations should still be a valuable aid in clinical practice and clinical research.

Sympathetic reflex latencies and conduction velocities in normal man.

(1) Micro-electrode recordings were made of multi-unit sympathetic activity in skin or muscle branches of the median nerve at the elbow and the peroneal nerve at the fibular head in 69 healthy subjects. In some recordings changes in skin resistance and pulse plethysmograms were monitored within the receptive field of the impaled fascicles. Conduction velocities in postganglionic sympathetic fibres were measured either directly in double nerve recordings (9 subjects) or indirectly by determining the latency of either of two sympathetic reflexes. For skin nerve sympathetic activity (SSA) the excitatory reflex response to an electrical skin stimulus was used and for muscle nerve sympathetic activity (MSA) the inhibitory baroreflex response to single arterial pulse waves. (2) For MSA, reflex latencies were 0.90--1.13 s in median and 1.22--1.54 s in peroneal nerve recordings. Corresponding latencies for SSA were 0.48--0.66 s and 0.72--0.91 s, respectively. Reflex latency showed a positive correlation with body height and with length of the extremity recorded from. From the correlation with extremity length, average conduction velocities for MSA in median and peroneal nerves were calculated to be 0.74 and 1.11 m/s, respectively. Corresponding figures for SSA were 1.69 and 1.16 m/s. (3) With direct determinations of conduction velocities average values for MSA (comprising mainly vasoconstrictor fibres) in median and peroneal nerves were 0.72 and 1.09 m/s, respectively. With direct SSA determinations, sympathetic bursts containing only vasoconstrictor impulses (giving plethysmographic responses but no changes of skin resistance) had lower conduction velocities than bursts containing only sudomotor impulses (giving electrodermal but no plethysmographic responses) or a mixture of sudomotor and vasoconstrictor impulses. Average values (0.77 and 1.27 m/s, respectively) were similar in median and peroneal recordings. (4) It is concluded that determination of reflex latency is a useful indirect measure of conduction velocity in sympathetic postganglionic fibres.

Sympathetic reflex latencies and conduction velocities in patients with polyneuropathy.

(1) Micro-electrode recordings of multi-unit sympathetic activity were attempted in skin or muscle branches of the peroneal nerve at the fibular head and the median nerve at the elbow in 41 patients with polyneuropathy of different causes. An indirect measure of sympathetic conduction velocity was obtained by determining the latency of either of two sympathetic reflexes. For skin nerve sympathetic activity (SSA) reflex responses to electrical skin stimuli were used and for muscle nerve sympathetic activity (MSA) reflex inhibition caused by the arterial pulse wave. The skin sympathetic function was also evaluated by measuring changes in skin resistance and finger/toe pulse plethysmograms. Motor conduction velocities were measured with surface electrodes. (2) In muscle (but not in skin) nerve fascicles afferent mass activity in myelinated fibres was often weak or absent. (3) There was a significant relationship between symptoms of autonomic impairment and impaired skin resistance and/or plethysmographic responses. There was also a relationship between impairment of these responses and failure to detect SSA. (4) Failure to find sympathetic activity occurred in 60% of diabetic patients but only in 27% of the whole material. When found, sympathetic activity had normal appearance and sympathetic reflex latencies were normal irrespective of degree of slowing of motor conduction velocity. (5) The results suggest that in polyneuropathy conduction velocities of post-ganglionic sympathetic fibres are normal as long as the fibres conduct. Degeneration of sympathetic fibres may be especially common in diabetic neuropathy.

Plasma exchange in patients with Guillain-Barré syndrome: clinical improvement in patients with serum IgG antibodies to peripheral nerve tissue.

The mixed hemagglutination technique was used to demonstrate IgG antibodies to peripheral nerve tissue in sera from patients with Guillain-Barré syndrome. The clinical effect and the effect on the antibodies of plasma exchange (PE) were examined in 24 patients, 16 patients with acute form and 8 patients with the chronic form of the disease. Neurological examination with muscle testing and neurophysiological examination of the patients were performed before and immediately after the PE. Before PE antibodies were detected in sera from 15 of the patients. These patients showed clinical improvement during the treatment, however in one of the patients only after a time interval of 2 weeks. After PE, antibodies were detected in sera from only 3 of the patients. The 9 patients without detectable antibodies showed no clinical improvement.